In 1989 a possible paramyxovirus etiology for giant cell hepatitis was proposed, based on electron micrographic changes seen in the livers of patients with this disease. Collaborative studies, including attempts to transmit the disease to primates, are in progress. Patients with thalassemia in Sardinia, Italy, receive monthly blood transfusions as therapy. Many of these patients have developed chronic hepatitis. Most cases could be identified as hepatitis B or hepatitis C, but some lacked markers of either of these viruses. These patients are being studied for evidence of previously unrecognized hepatitis viruses. Patients with fulminant non-A, non-B hepatitis generally do not have evidence of infection with any recognized hepatitis virus. Only about 10% can be identified as having fulminant hepatitis C. The remaining 90% remain a diagnostic enigma and may be infected with one or more previously unrecognized viruses. In collaborative studies, we are attempting to transmit the disease to primates. The objectives of this project are to identify and characterize new etiologic agents of hepatitis and to develop useful assays for diagnosis of infection and seroepidemiologic studies. A longer term objective is the development of passive and active immunoprophylaxis for these important human pathogens.